This project aims to elucidate epigenetic and transcriptional mechanisms in the reward brain circuitry which mediate long-term pain states and responses to antidepressant medications. Neuropathic pain is a chronic condition characterized by sensory, cognitive and affective symptoms. Most of the drugs used to treat the pain-like symptoms of this disorder demonstrate low efficacy and major side-effects. And, well documented among classes of opioids many of the current treatments can lead to debilitating addiction. There is a pressing need for the development of more efficacious and better tolerated medications for chronic neuropathic pain. Tricyclic antidepressants (TCAs) and the selective, serotonin/norepinephrine reuptake inhibitors (SNRIs) contain both antiallodynic and antidepressant properties; however, they demonstrate slow onset of action and longtime usage often is accompanied by severe adverse effects. Understanding the intracellular mechanisms mediating the actions of TCAs and SNRIs will help the development of novel and more efficacious medications for the treatment of neuropathic pain. Our earlier findings identified a key role of the epigenetic modifier Histone deacetylase 5 (HDAC5) in the onset of action and efficacy of TCAs/SNRIs in models of neuropathic pain. HDAC5 in the Nucleus Accumbens (NAc) binds to chromatin complexes to suppress the expression of several genes that affect synaptic function, including the transcription factor MEF2C. Our recent preliminary findings suggest that promotion of MEF2C activity in the NAc leads to recovery from neuropathic pain states. Moving forward, we propose to use genetic mouse models, biochemical and genomic approaches to understand the impact of chronic pain in the nuclear activity of HDAC5, and the NAc circuits associated with HDAC5 actions. Furthermore, we will test known HDAC5 target genes, such as MEF2C, for their ability to promote recovery from chronic pain states and enhance the efficacy of antidepressants. We will employ genomic approaches to identify additional HDAC5 targets and test for their role in chronic pain and SNRI efficacy. Our findings will help to provide insights regarding epigenetic and transcriptional mechanisms that control the maintenance of chronic pain and responsiveness to pain-alleviating drugs.